(380x) Overcoming the Limitations of Hydrochlorothiazide Micronization Using the Precipitation with Compressed Fluid Antisolvent Process

When a patient is prescribed with medication, the dosage considers how much medication is needed to exhibit its therapeutic effect while not inducing toxic or lethal effects. However, many essential drugs are poorly soluble. These drugs may not be available to system when needed due to the slow dissolution rates or may even be excreted from the body. Therefore, many times, the drugs are prescribed at higher dosages than the needed amount. To lower the dosage of these drugs, chemical and physical modifications can be applied. The latter option is preferred as chemical modifications, which alter the chemical structures to enhance solubility, require time consuming repetitions of the drugs’ clinical trials. Therefore, many researches are focused on physical modifications to improve the dissolution rate of the poorly soluble drugs, which is most often the rate determining step for drug absorption. Conventionally, milling and spray drying have been used to decrease the particle size of the drugs. However, limitations of these processes include drug degradation, residual solvent, and high drug yields (when excipients are utilized).

To overcome these restrictions, this research utilized the precipitation with compressed fluid antisolvent process under sub-and supercritical conditions. The model drug, Hydrochlorothiazide(HCT), is classified as poorly soluble by the Biopharmaceutics Classification System. Miconization of neat HCT yielded agglomerated, irregular microparticles. While the particle size decreased, not much difference was observed in the dissolution rate. Therefore, to further decrease the particle size, HCT was coprecipitated with a water soluble polymer, polyvinylpyrrolidone (PVP). As a result, uniform, spherical nanoparticles that significantly enhanced the dissolution rate of HCT were obtained. FT-IR results show no sign of residual solvent, which is crucial for the drug’s stability and toxicity. A combination of HR-TEM and the dissolution tests revealed that the particles are composed of PVP particles that contain HCT. Even though an excipient was used, the products showed high normalized drug loadings and precipitation yields. These results suggest that HCT particles precipitated on the PVP particles by heterogeneous nucleation.